Dear Editor:
The second-generation antipsychotics (SGAs) that focus on dopamine-2 plus serotonin-2A receptor antagonism are first-line treatments in psychiatric diseases, with lower risk of extrapyramidal symptoms compared to first-generation antipsychotics. However, SGAs, most of which inhibit a range of other receptors, have differing levels of increased risk for weight gain, dyslipidemia, and Type 2 diabetes mellitus (T2DM).1 In one study, a significant association between weight gain and receptor affinity of antidepressants was observed in the models for histamine-H1 (H1), serotonin-2C (5-HT2C), muscarinic-3 (M3), and adrenergic- alpha-1A (α1A) receptors.2 In another study, a positive association was found between H1, M3, and, 5-HT2C receptor occupancies and reports of antipsychotic-induced diabetes.3 Furthermore, changes in lipid and glucose levels might arise secondary to weight gain or occur independently of weight change during treatment with antipsychotics.4
To investigate the variety of metabolic effects regarding multiacting receptor targeted antipsychotics (MARTAs), patients with schizophrenia who were switched from olanzapine to asenapine or clozapine without an alternation of other medications were recruited. The ethics committee of Kusatsu Hospital, Hiroshima, Japan, approved this study. Informed consent was received from all study participants.
Research outline. Eight male and two female subjects with a mean age of 42.8 years who were switched from olanzapine to asenapine and eight male and four female subjects with a mean age of 41.2 years who were switched from olanzapine to clozapine entered the study. Fasting plasma glucose (FBS), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and body weight were measured at baseline, one month, and three months after switching treatment. The ratio of TG to HDL-C values (TG/HDL-C) reflecting insulin resistance was assessed together with these metabolic values. Multiple comparisons were performed with repeated measured analysis of variance (ANOVA), followed by post-hoc analysis.
The TG levels and TG/HDL-C ratios tended to increase and TG levels significantly increased at three months from baseline in both groups, whereas body weight, LDL-C, and HDL-C levels remained unchanged throughout. The FBS levels significantly increased at one and three months from baseline in the clozapine group, and consistently decreased in the asenapine group, although not significantly (Table 1 and Figure 1).
TABLE 1.
Anthropometric and metabolic measures for subjects with follow-up data
| METABOLIC MEASURE | MONTH | ASENAPINE | CLOZAPINE | P | ||
|---|---|---|---|---|---|---|
| OUTCOME | P | OUTCOME | P | |||
| BW, kg | Baseline | 65.5±4.1 | n/a | 60.9±2.8 | n/a | 0.468 |
| 1 | 62.7±4.0 | 0.634 | 59.8±2.4 | 0.772 | ||
| 3 | 65.4±4.3 | 0.985 | 61.9±2.7 | 0.793 | ||
| TG, mg/dL | Baseline | 72.4±9.8 | n/a | 91.4±12.8 | n/a | 0.177 |
| 1 | 80.6±6.5 | 0.698 | 101.5±12.6 | 0.575 | ||
| 3 | 120.1 ±22.5 | 0.030 | 129.9±12.7 | 0.039 | ||
| LDL-C, mg/dL | Baseline | 98.1 ± 7.2 | n/a | 99.2±6.8 | n/a | 0.999 |
| 1 | 101.3±7.6 | 0.748 | 98.8±6.2 | 0.969 | ||
| 3 | 92.6±6.1 | 0.580 | 101.2±6.1 | 0.825 | ||
| HDL-C, mg/dL | Baseline | 55.1 ±4.7 | n/a | 55.0±5.9 | n/a | 0.499 |
| 1 | 56.1 ±3.3 | 0.883 | 55.7±5.7 | 0.932 | ||
| 3 | 55.3 ±5.9 | 0.974 | 56.9±6.5 | 0.824 | ||
| TG/HDL | Baseline | 1.45±0.26 | n/a | 2.03±0.48 | n/a | 0.337 |
| 1 | 1.49±0.16 | 0.949 | 2.16±0.42 | 0.833 | ||
| 3 | 2.56±0.65 | 0.072 | 2.68±0.39 | 0.290 | ||
| FBS, mg/dL | Baseline | 93.5±4.8 | n/a | 78.2±2.4 | n/a | 0.004 |
| 1 | 86.1 ±4.6 | 0.220 | 89.5±2.9 | 0.002 | ||
| 3 | 82.0±2.4 | 0.069 | 85.2±1.6 | 0.043 | ||
Values are mean±SE unless otherwise specified
P values: for two groups comparisons at baseline with unpaired, Mann-Whitney U test
P values: for intragroup comparisons for each time point relative to the baseline values with Fisher's protected least significant difference
P or P values are considered statistically significant at <0.05
n/a: not applicable; BW: body weight; FBS: fasting blood glucose; HDL-C: high-density lipoprotein cholestrol; LDL-C: low-density lipoprotein choloestrol; TG: triglyceride; TG/HDL: ratio of TG to HDL-C
Figure 1.
Changes in the levels of triglyceride and fasting blood glucose in asenapine or clozapine switching from olanzapine, at baseline and 1 and 3 months
*P<0.05 for intragroup comparisons for each time point relative to the baseline values
**P<0.01 for intragroup comparisons for each time point relative to the baseline values
ASE: asenapine; CLZ: clozapine; TG: triglyceride; FBS: fasting blood glucose; (0): baseline; (1): 1 month; (3): 3 month
Discussion. The strength of this study was that MARTAs can directly affect lipid and glucose levels, independent of weight gain and insulin resistance. Among in-vitro receptor-binging profiles,5 antagonism 5-HT2C and M3 were suggested to play major roles on each metabolic abnormality. Because the potency of 5HT2C receptor blockade of asenapine and clozapine exceeds that of olanzapine, the potency of M3 receptor blockade becomes stronger in order of clozapine, olanzapine, and asenapine (Table 2).
TABLE 2.
Quantitative comparison of receptor profile among asenapine, clozapine, and olanzapine
| DRUG | D2L/5-HT2A | D2L/5-HT2C | D2L/α1A | D2L/H1 | D2L/M3 |
|---|---|---|---|---|---|
| Asenapine (Ki/Ki) | 17.80 | 36.31 | 1.08 | 1.26 | 0.000059 |
| Clozapine (Ki/Ki) | 33.17 | 49.09 | 10.71 | 77.59 | 5.51 |
| Olanzapine (Ki/Ki) | 16.21 | 5.50 | 0.96 | 6.31 | 0.63 |
The Ki for D2L receptor/Ki for each receptor ratio indicated the affinity to each receptor as a standard with dopamine D2L.
D2L: dopamine-2 long isoform receptor; H1: histamine-H1 receptor; M3: muscarinic-3 receptor; 5-HT2A: serotonin-2A receptor; 5-HT2C: serotonin-2C receptor; α1A: alpha-1A receptor
The 5-HT2C receptor is one of the most intriguing members of the G protein-coupled receptor superfamily that is clearly affected by a number of established antidepressants/antipsychotics, and it might be one of the culprits in antipsychotic-induced weight gain.6 Though the receptor-binding profiles regarding SGA-associated dyslipidemia are not fully understood, studies using mice with a genetic disruption of serotonin 5-HT2C receptor showed a reduced central sympathetic outflow and substantial reductions in the energy cost, which resulted in hyperlipidemia.7 Affinity for the cholinergic muscarinic M3 receptor subtype was presented as the best predictor for the propensity of antipsychotics to induce T2DM.8 Antagonism of M3 receptors, which control cholinergic-stimulated pancreatic insulin secretion, have been associated with glucose intolerance and development of hyperglycemia.9
Limitations. The retrospective, observational method; small sample size; co-medication; baseline differences in glucose levels; and lack of insulin levels were limitations in this study.
Conclusion. The relationships between the potency of 5-HT2C blockade and hypertriglyceridemia and the potency of M3 blockade and glucose intolerance were shown in clinical setting. Receptor-binging profiles might be useful to estimate metabolic effect of antipsychotics-treatment.
REFERENCES
- 1.Meyer JM, Davis VG, Goff DC, et al. Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: prospective data from phase 1. Schizophr Res. 2008;101:273–286. doi: 10.1016/j.schres.2007.12.487. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Salvi V, Mencacci C, Barone-Adesi F. H1-histamine receptor affinity predicts weight gain with antidepressants. Eur Neuropsychopharmacol. 2016;26:1673–1677. doi: 10.1016/j.euroneuro.2016.08.012. [DOI] [PubMed] [Google Scholar]
- 3.Montastruc F, Palmaro A, Bagheri H, et al. Role of serotonin 5-HT2C and histamine H1 receptors in antipsychotic-induced diabetes: s pharmacoepidemiological-pharmacodynamic study in VigiBase. Eur Neuropsychopharmacol. 2015;25:1556–1565. doi: 10.1016/j.euroneuro.2015.07.010. [DOI] [PubMed] [Google Scholar]
- 4.De Hert M, Yu W, Detraux J, et al. Body weight and metabolic adverse effects of asenapine, iloperidone, lurasidone and paliperidone in the treatment of schizophrenia and bipolar disorder: a systematic review and exploratory meta-analysis. CNS Drugs. 2012;26:733–759. doi: 10.2165/11634500-000000000-00000. [DOI] [PubMed] [Google Scholar]
- 5.Shahid M, Walker GB, Zorn SH, Wong EH. Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. J Psychopharmacol. 2009;23:65–73. doi: 10.1177/0269881107082944. [DOI] [PubMed] [Google Scholar]
- 6.Palacios JM, Pazos A, Hoyer D. A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment. Psychopharmacology (Berl). 2017;234:1395–1418. doi: 10.1007/s00213-017-4545-5. [DOI] [PubMed] [Google Scholar]
- 7.Nonogaki K, Abdallah L, Goulding EH, et al. Hyperactivity and reduced energy cost of physical activity in serotonin 5-HT2C receptor mutant mice. Diabetes. 2003;52:315–320. doi: 10.2337/diabetes.52.2.315. [DOI] [PubMed] [Google Scholar]
- 8.Silvestre JS, Prous J. Research on adverse drug events. I. Muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes. Methods Find Exp Clin Pharmacol. 2005;27:289–304. doi: 10.1358/mf.2005.27.5.908643. [DOI] [PubMed] [Google Scholar]
- 9.Tran YH, Schuiling-Veninga CCM, Bergman JE, et al. Impact of muscarinic M3 receptor antagonism on the risk of Type 2 diabetes in antidepressant-treated patients: A case-controlled study. CNS Drugs. 2017;316:483–493. doi: 10.1007/s40263-017-0436-x. [DOI] [PMC free article] [PubMed] [Google Scholar]